{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T20:26:37Z","timestamp":1789244797490,"version":"build-2803163510"},"reference-count":54,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","license":[{"start":{"date-parts":[[2021,8,1]],"date-time":"2021-08-01T00:00:00Z","timestamp":1627776000000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2021,8]]},"abstract":"<jats:sec>\n            <jats:title>Background and Aims<\/jats:title>\n            <jats:p>Primary biliary cholangitis (PBC) is a prototypical organ\u2010specific autoimmune disease that is mediated by autoreactive T\u2010cell attack and destruction of cholangiocytes. Despite the clear role of autoimmunity in PBC, immune\u2010directed therapies have failed to halt PBC, including biologic therapies effective in other autoimmune diseases. MicroRNA (miRNA) dysregulation is implicated in the pathogenesis (PBC). In the dominant\u2010negative TGF\u2010\u03b2 receptor type II (dnTGF\u03b2RII) mouse model of PBC, autoreactive CD8 T cells play a major pathogenic role and demonstrate a striking pattern of miRNA down\u2010regulation. Enoxacin is a small molecule fluoroquinolone that enhances miRNA biogenesis, partly by stabilizing the interaction of transactivation response RNA\u2010binding protein with Argonaute (Ago) 2.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Approach and Results<\/jats:title>\n            <jats:p>We hypothesized that correcting aberrant T\u2010cell miRNA expression with enoxacin in dnTGF\u03b2RII mice could modulate autoreactive T\u2010cell function and prevent PBC. Here, we show that liver\u2010infiltrating dnTGF\u03b2RII CD8 T cells have significantly decreased levels of the miRNA biogenesis molecules prolyl 4\u2010hydroxylase subunit alpha 1 (P4HA1) and <jats:italic toggle=\"yes\">Ago2<\/jats:italic> along with significantly increased levels of granzyme B and perforin. Enoxacin treatment significantly up\u2010regulated miRNAs in dnTGF\u03b2RII CD8 T cells and effectively treated autoimmune cholangitis in dnTGF\u03b2RII mice. Enoxacin treatment directly altered T cells both <jats:italic toggle=\"yes\">ex vivo<\/jats:italic> and <jats:italic toggle=\"yes\">in vitro<\/jats:italic>, resulting in altered memory subset numbers, decreased proliferation, and decreased interferon\u2010\u03b3 production. Enoxacin significantly decreased CD8 T\u2010cell expression of the transcription factor, <jats:italic toggle=\"yes\">Runx3<\/jats:italic>, and significantly decreased perforin expression at both the mRNA and protein levels.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>Enoxacin increases miRNA expression in dnTGF\u03b2RII CD8 T cells, reduces CD8 T\u2010cell pathogenicity, and effectively halted progression of autoimmune biliary disease. Targeting the miRNA pathway is a therapeutic approach to autoimmunity that corrects pathological miRNA abnormalities in autoreactive T cells.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.31724","type":"journal-article","created":{"date-parts":[[2021,1,19]],"date-time":"2021-01-19T03:21:47Z","timestamp":1611026507000},"page":"835-846","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":17,"title":["Enoxacin Up\u2010Regulates MicroRNA Biogenesis and Down\u2010Regulates Cytotoxic CD8 T\u2010Cell Function in Autoimmune Cholangitis"],"prefix":"10.1097","volume":"74","author":[{"given":"Arata","family":"Itoh","sequence":"first","affiliation":[{"name":"Division of Immunology, Allergy and Rheumatology,University of Cincinnati College of Medicine,Cincinnati,OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Adams","sequence":"additional","affiliation":[{"name":"Division of Immunology, Allergy and Rheumatology,University of Cincinnati College of Medicine,Cincinnati,OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenting","family":"Huang","sequence":"additional","affiliation":[{"name":"Division of Immunology, Allergy and Rheumatology,University of Cincinnati College of Medicine,Cincinnati,OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuehong","family":"Wu","sequence":"additional","affiliation":[{"name":"Division of Immunology, Allergy and Rheumatology,University of Cincinnati College of Medicine,Cincinnati,OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kritika","family":"Kachapati","sequence":"additional","affiliation":[{"name":"Division of Immunology, Allergy and Rheumatology,University of Cincinnati College of Medicine,Cincinnati,OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyle J.","family":"Bednar","sequence":"additional","affiliation":[{"name":"Division of Immunology, Allergy and Rheumatology,University of Cincinnati College of Medicine,Cincinnati,OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick S. C.","family":"Leung","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Allergy and Clinical Immunology,University of California, Davis,Davis,CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3193-6851","authenticated-orcid":false,"given":"Weici","family":"Zhang","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Allergy and Clinical Immunology,University of California, Davis,Davis,CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard A.","family":"Flavell","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine,Yale University School of Medicine,New Haven,CT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. 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